Brachytherapy is a general term, covering medical treatment which involves placement of a radioactive source near a diseased tissue, and may involve the temporary or permanent implantation or insertion of a radioactive source into the body of a patient. The radioactive source is thereby located in proximity to the area of the body to be treated. This has the advantage that a high dose of radiation may be delivered to the treatment site with relatively low dosages of radiation to surrounding or intervening healthy tissue.
Brachytherapy has been proposed for use in the treatment of a variety of conditions, including arthritis and cancer, for example breast, brain, liver and ovarian cancer, and especially prostate cancer in men (see for example J. C. Blasko et al., The Urological Clinics of North America, 23, 633–650 (1996), and H. Ragde et al., Cancer, 80, 442–453 (1997)). Prostate cancer is the most common form of malignancy in men in the USA, with more than 44,000 deaths in 1995 alone. Treatment may involve the temporary implantation of a radioactive source for a calculated period, followed by its subsequent removal. Alternatively, the radioactive source may be permanently implanted in the patient and left to decay to an inert state over a predictable time. The use of temporary or permanent implantation depends on the isotope selected and the duration and intensity of treatment required.
Permanent implants for prostate treatment comprise radioisotopes with relatively short half-lives and lower energies relative to temporary sources. Examples of permanently implantable sources include iodine-125 or palladium-103 as the radioisotope. The radioisotope is generally encapsulated in a titanium casing to form a “seed” which is then implanted. Temporary implants for the treatment of prostate cancer may involve iridium-192 as the radioisotope.
Recently brachytherapy, in particular intraluminal radiation therapy has been proposed for the treatment of restenosis (for reviews see R. Waksman, Vascular Radiotherapy Monitor, 1998, 1, 10–18, and MedPro Month, January 1998, pages 26–32). Restenosis is a re-narrowing of the blood vessels after initial treatment of coronary artery disease. Various isotopes including iridium-192, strontium-90, yttrium-90, phosphorous-32, rhenium-186 and rhenium-188 have been proposed for use in treating restenosis.
Conventional radioactive sources for use in brachytherapy include so-called seeds. Seeds are smooth sealed sources, which comprise containers or capsules of a biocompatible material (e.g. metals such as titanium or stainless steel), containing a radioisotope within a sealed chamber. The container or capsule material permits radiation to exit through the container/chamber walls (U.S. Pat. Nos. 4,323,055 and 3,351,049). Such seeds are only suitable for use with radioisotopes which emit radiation which can penetrate the chamber/container walls. Therefore, such seeds are generally used with radioisotopes which emit γ-radiation or low-energy X-rays, rather than with β-emitting radioisotopes.
In brachytherapy, it is vital to the therapeutic outcome for the medical personnel administering the treatment to know the relative position of the radioactive source in relation to the tissue to be treated, i.e. to ensure that the radiation is delivered to the correct tissue and that no localised over or under dosing occurs. Current seeds therefore typically incorporate a marker for X-ray imaging such as a radio-opaque metal (e.g. silver, gold or lead). The location of the implanted seed is then established via X-ray imaging, which exposes the patient to an additional radiation dose. Such radio-opaque markers are typically shaped so that imaging gives information on the orientation as well as location of the seed in the body, since both are necessary for accurate radiation dosimetry calculations.
Permanent implantation of brachytherapy radioactive sources for the treatment of, for example, prostate cancer may be done using an open laparotomy technique with direct visual observation of the radioactive sources and the tissue. However, the procedure is relatively invasive and often leads to undesirable side effects in the patient. An improved procedure comprising transperineal insertion of radioactive sources into predetermined regions of the diseased prostate gland (using an external template to establish a reference point for implantation) has been proposed. See for example Grimm, P. D., et al., Atlas of the Urological Clinics of North America, Vol. 2, No. 2, 113–125 (1994). Commonly, these radioactive sources, for example seeds, are inserted by means of a needle device while an external depth gauge is employed with the patient in the dorsal lithotomy position. For prostate cancer treatment, typically 50 to 120 seeds are administered per patient in a 3-dimensional array derived from multiple needle insertions of linear, spaced seeds. The dose calculation is based on this complex 3-D array, plus data on the tumour volume plus prostate volume etc.
Preferably, the insertion or implantation of a radioactive source for brachytherapy is carried out using minimally-invasive techniques such as, for example, techniques involving needles and/or catheters. It is possible to calculate a location for each radioactive source, which will give the desired radiation dose profile. This can be done using a knowledge of the radioisotope content of each source, together with the dimensions of the source, accurate dimensions of the tissue or tissues in relation to which the source is to be placed, plus the position of said tissue relative to a reference point. The dimensions of tissues and organs within the body for use in such dosage calculations may be obtained prior to placement of the radioactive source by using conventional diagnostic imaging techniques including X-ray imaging, magnetic resonance imaging (MRI) and ultrasound imaging. However, difficulties may arise during the radioactive source placement procedure which may adversely affect the accuracy of the placement of the source if only pre-placement images are used to guide the source placement. For example, tissue volume may change as a result of swelling or draining of fluid to and from the tissue. Tissue position and orientation can change in the patient's body relative to a selected internal or external reference point as a result of for example manipulation during surgical procedures, movement of the patient or changes in the volume of adjacent tissue. Thus, it is difficult to achieve accurate placement of sources to achieve a desired dosage profile in brachytherapy using only knowledge of tissue anatomy and position that was obtained prior to the placement procedure. Therefore, it is advantageous if real-time visualisation of both the tissue and the radioactive source can be provided. A particularly preferred imaging method due to its safety, ease of use and low cost, is ultrasound imaging.
During the placement of the radioactive sources into position, the surgeon can monitor the position of tissues such as the prostate gland using, for example, transrectal ultrasound pulse-echo imaging techniques which offer the advantage of low risk and convenience to both patient and surgeon. The surgeon can also monitor the position of the relatively large needle used in implantation procedures using ultrasound. During the implantation or insertion procedure, the location of the source may be inferred to be proximal to the tip of the needle or other device used for the procedure. However, the relative location of each separate radioactive source should be evaluated subsequent to the implantation procedure to determine if it is in a desired or undesired location and to assess the uniformity of the therapeutic dose of radiation to the tissue. Radioactive sources may migrate within the tissue following implantation.
Ultrasound reflections may be either specular (mirror-like) or scattered (diffuse). Biological tissue typically reflects ultrasound in a scattered manner, whilst metallic devices tend to be effective reflectors of ultrasound. Relatively large smooth surfaces such as those of needles used in medical procedures reflect sound waves in a specular manner. The ultrasound visibility of conventional radioactive seeds is highly dependent upon the angular orientation of the seed axis with respect to the ultrasound transducer used for imaging. The ultrasound reflection from a surface is dependent on the surface shape and can be deduced from diffraction considerations. Thus, a smooth flat surface will generally act as a mirror, reflecting ultrasound waves in the wrong direction unless the angle between the sound and the surface is 90°. A smooth cylindrical structure such as a conventional radioactive seed will reflect waves in a fan shaped conical pattern pointing away from the transducer, but will only give strong ultrasound reflections when imaged at an angle very close to 90°.
Thus, brachytherapy seeds with a smooth titanium surface are effective ultrasound reflectors, but the reflected ultrasound intensity is strongly dependent on the orientation of the seed with respect to the ultrasound beam. Theory and practical experiments show that even at an angle of 8 degrees between the long axis of the seed and the ultrasound transducer (a deviation of 8° from orthogonal), the signal intensity drops by a factor of 100 (20 dB), and the seed becomes difficult to detect. At an orientation of 10 degrees the seed is not possible to detect against a tissue background. Consequently, even very small deviations from orthogonal incidence of the ultrasound beam cause substantial reductions in the intensity of the echo signal. Analysis of clinical X-ray images of the prostate acquired post seed implantation show a wide distribution of seed angular orientations and only a fraction of the seeds are oriented within ±10 degrees.
Thus, the relatively small size of current brachytherapy radioactive sources and the specular reflection properties of their surfaces makes them very difficult to detect by ultrasound imaging techniques.
There is therefore a need for radioactive sources for use in brachytherapy with improved ultrasound imaging visibility, and in particular for sources where the dependence of visibility on the angular orientation of the axis of the source with respect to the ultrasound transducer is reduced. Since the total returned echo intensity is limited by the physical size of the seed, improvements require broadening the angular range of echo return. The present invention provides radioactive sources with improved ultrasound visibility, by reducing the angular dependence of the reflected ultrasound.
Efforts have been made to enhance the ultrasound visibility of surgical apparatus which is relatively larger than seeds, (e.g. surgical needles, solid stylets and cannulae) by suitable treatment of their surfaces such as roughening, scoring or etching. Thus, U.S. Pat. No. 4,401,124 discloses a surgical instrument (a hollow needle device) that has a diffraction grating inscribed on the surface to enhance the reflection coefficient of the surface. Sound waves that strike the grooves are diffracted or scattered as secondary wave fronts in many directions, and a percentage of these secondary waves are detected by the ultrasound transducer. The diffraction grating is provided for use at the leading edge of a surgical instrument for insertion within a body, or for use along a surface of an object the position of which is to be monitored while in the body.
U.S. Pat. No. 4,869,259 discloses a medical needle device that has a portion of its surface particle-blasted to produce a uniformly roughened surface that scatters incident ultrasound, such that a portion of the scattered waves is detected by an ultrasound transducer.
U.S. Pat. No. 5,081,997 discloses surgical instruments with sound reflective particles imbedded in a portion of the surface. The particles scatter incident sound, and a portion is detected by an ultrasound transducer.
U.S. Pat. No. 4,977,897 discloses a tubular cannula device comprising a needle and an inner stylet in which one or more holes are cross-drilled perpendicular to the axis of the needle to improve ultrasound visibility. The solid inner stylet may be roughened or scored to enhance the sonographic visibility of the needle/stylet combination.
WO 98/27888 describes a echogenically enhanced medical device in which a print pattern mask of non-conductive epoxy-containing ink is transfer-coated to the surface of the device, flash dried, and then thermally crosslinked. Portions of the needle not protected by the mask are removed by etching in an electropolishing step to leave a pattern of substantially square depressions in the bare metal, and the ink masked is removed with a solvent and mechanical scrubbing. The depressions provide the device with enhanced echogenicity under ultrasound.
U.S. Pat. No. 4,805,628 discloses a device which is inserted or implanted for long-term residence in the body, which device is made more visible to ultrasound by providing a space in the device which has a substantially gas impermeable wall, such space being filled with a gas or mixture of gases. The invention is directed to IUD's (intrauterine devices), prosthetic devices, pacemakers, and the like.
McGahan, J. P., in “Laboratory assessment of ultrasonic needle and catheter visualisation.” Journal of Ultrasound In Medicine, 5(7), 373–7, (July 1986) evaluated seven different catheter materials for their sonographic visualisation in vitro. While five of the seven catheter materials had good to excellent sonographic detection, nylon and polyethylene catheters were poorly visualised. Additionally, various methods of improved needle visualisation were tested. Sonographic needle visualisation was aided by a variety of methods including either roughening or scoring the outer needle or inner stylet and placement of a guide wire through the needle.
WO 00/28554, which is commonly assigned to the present assignee, discloses roughened brachytherapy sources, including seeds, which exhibit enhanced echogenicity. This disclosure shows that the ultrasound visibility of radioactive sources suitable for use in brachytherapy can be improved, even though such sources are relatively much smaller than needles, catheters etc.
Once implanted, seeds are intended to remain permanently at the site of implantation. However, individual seeds may, on rare occasions, migrate within a patient's body away from the initial site of implantation or insertion. This is highly undesirable from a clinical perspective, as it may lead to underdosing of a tumour or other diseased tissue and/or unnecessary exposure of healthy tissue to radiation. There is therefore also a need for radioactive sources for use in brachytherapy which show a reduced tendency to migrate within a patient's body when compared to conventional brachytherapy seeds.
Parameters such as the amplitude and shape of surface irregularities and the distance between repeating surface pattern details determine the angular dependency of echo reflections. As part of the present invention, a large number of prototype samples have been evaluated and a narrow range of seed design options has been identified. A range of surface shapes have been tested: circular and helical sinusoidal and square grooves, triangular grooves, dimples and sandblasted surfaces. Profiles with sharp corners were found to widen the angular range more than smooth shapes. Dimpled surfaces were not found to work as well as grooved surfaces.